Nicotine dependence is the leading preventable cause of mortality in the world today. Cue-induced craving is likely to play an important role in relapse. The neural correlates of smoking cue-induced craving and extinction have been elucidated using fMRI. Recent advances make it possible to utilize real-time fMRI (rtfMRI) feedback to modify behavior, cognitions and regional brain activity. The purpose of this application is to develop the imaging parameters, brain-computer interface and standardized procedures for using rtfMRI with visual feedback to help nicotine-dependent individuals decrease craving when presented with smoking cues. The exploratory nature of this study requires a phased approach. Phase 1 will focus on the development of the technology and study paradigm. In order to proceed to Phase 2, there must be convincing evidence that a substantial proportion of nicotine-dependent individuals can manipulate brain activity in critical brain regions associated with smoking cue-induced craving based on rtfMRI visual feedback. If this is established, a controlled comparison and duration of effect will be explored in Phase 2. This project will set the stage for clinical trials investigating a very innovative approach to the treatment of nicotine dependence and other substance use disorders. The study will provide critical information about optimal techniques, durability and "transferability" of the effects to situations outside of the scanner. The findings of this study can be used to inform the design of a clinical trial to investigate the use of rtfMRI neuromodulation training in smoking cessation. PUBLIC HEALTH RELEVANCE: Improving treatment for nicotine dependence will provide substantial public health benefit as nicotine dependence is the leading preventable cause of mortality in the world today. Moreover, if individuals can learn to modulate activity in critical brain regions that control urges and craving states, this could have applicability in a broad range of disease states with major public health significance (i.e. other substance use disorders, obesity).